An evaluation of some of the mechanisms underlying the physiological regulation of the fibrinolytic enzyme system will be undertaken. The proposed research will focus on two regulatory aspects: 1) those human plasma inhibitory factors which tend to buffer the active enzyme plasmin; and 2) those elements involved with the production and maintenance of circulating levels of the zymogen, plasminogen. Using highly purified human enzyme and inhibitor preparations, a systematic and comparative study will be made of the kinetics of plasmin inhibition by each of the plasma protease inhibitors. The methods involved will focus primarily on enzymatic assays and gel electrophoresis. In addition, the relative contributions that each of the inhibitors makes to the total antiplasmin inhibitory capacity of plasma will be determined using a whole plasma system and radiolabelled inhibitors. The interaction of these inhibitors with the activation of plasminogen to plasmin will also be studied. The final aspect of the proposed research will focus on the isolation and characterization of a plasma factor, which I have previously determined, functions as a stimulator of plasminogen production and/or release after acute depletion of the zymogen in cats. The results of the proposed experiments could have great clinical importance in regard to fibrinolytic therapy and should provide a clue as to how this system functions in normal as well as pathological situations.